Pulmonary calcification and ossification occurs with a number of systemic and pulmonary conditions. Specific symptoms are often lacking, but calcification may be a marker of disease severity and its chronicity. Pathophysiologic states predisposing to pulmonary calcification and ossification include hypercalcemia, a local alkaline environment, and previous lung injury. Factors such as enhanced alkaline phosphatase activity, active angiogenesis, and mitogenic effects of growth factors may also contribute. The clinical classification of pulmonary calcification includes both metastatic calcification, in which calcium deposits in previously normal lung or dystrophic calcification, which occurs in previously injured lung. Pulmonary ossification can be idiopathic or can result from a variety of underlying pulmonary, cardiac, or extracardiopulmonary disorders. The diagnosis of pulmonary calcification and ossification requires various imaging techniques, including chest radiography, computed tomographic scanning, and bone scintigraphy. Interpretation of the presence of and the specific pattern of calcification or ossification may obviate the need for invasive biopsy. In this review, specific conditions causing pulmonary calcification or ossification that may impact diagnostic and treatment decisions are highlighted. These include metastatic calcification caused by chronic renal failure and orthotopic liver transplantation, dystrophic calcification caused by granulomatous disorders, DNA viruses, parasitic infections, pulmonary amyloidosis, vascular calcification, the idiopathic disorder pulmonary alveolar microlithiasis, and various forms of pulmonary ossification.
Clinical Classification of Pulmonary Calcification and Ossifi- cation
Proposed Mechanisms of Ectopic Lung Calcification and Os- sification
Role of Relative and Absolute Calcium Excess
Role of an Alkaline Environment
Role of Lung Injury or Fibrosis
Role of Angiogenesis
99mTc-MDP Bone Scintigraphy
Pulmonary Metastatic Calcification
Pulmonary Calcification Associated with Granulomatous Disorders
Pulmonary Calcification as a Sequela of Varicella or Other Viral Pneumonias
Pulmonary Calcification Associated with Parasitic Infections
Pulmonary Calcification Associated with Amyloidosis
Pulmonary Vascular Calcification
Pulmonary Alveolar Microlithiasis
Although direct observation and palpation of thoracic calcification were noted by Laennec in his textbook of physical examination of the lungs (1), the interest in pulmonary calcification began with the advent of chest radiography in the late 19th century (2).
Calcification within the thorax results from disparate clinical states. The anatomic location and specific features of the calcification often provide insights into occult diseases and can sometimes explain respiratory symptoms. Ectopic calcification occurs in the chest wall, pleura, lung parenchyma, hilar and mediastinal lymph nodes, and pulmonary arteries (3). This review organizes the classification of the pulmonary parenchymal calcific and ossific disorders, outlines their probable or possible pathogenesis, summarizes methods of detection, and illustrates their clinico–radiographic–pathologic features. A discussion of calcified solitary pulmonary nodules is not included. The potential impact of calcification on diagnosis and treatment is highlighted whenever specific information is available.
Calcification refers to the deposition of calcium salts in tissues, in contrast to ossification, which indicates bone tissue formation (calcification in a collagen matrix), with or without marrow elements. A number of pathologic conditions predispose to soft tissue calcification. Internal organs most commonly affected by ectopic calcification include the stomach, kidneys, lungs, heart, and blood vessels. The lungs seem particularly susceptible to this complication. Pathologic soft tissue calcification can be broadly divided into either (1) metastatic calcification, in which calcium deposits in normal tissues, or (2) dystrophic calcification, in which calcification is superimposed on previously injured lung (Table 1)
|A. Benign causes|
|1. Chronic renal insufficiency on hemodialysis|
|2. Orthotopic liver transplantation|
|3. Primary hyperparathyroidism|
|4. Excess exogenous administration of calcium and vitamin D (milk-alkali syndrome)|
|5. Hypervitaminosis D|
|7. Osteitis deformans (Paget's disease)|
|B. Malignant causes|
|1. Parathyroid carcinoma|
|2. Multiple myeloma|
|4. Hypopharyngeal squamous cell carcinoma|
|5. Synovial sarcoma|
|6. Breast carcinoma|
|II. Dystrophic calcification|
|A. Granulomatous disorders|
|B. Viral infections|
|1. Postvaricella pneumonia|
|2. Smallpox handler's lung|
|C. Parasitic infections|
|E. Pulmonary vascular calcifications|
|1. Vascular grafts|
|2. Pulmonary hypertension|
|3. Congenital high flow|
|F. Coal worker's pneumoconiosis|
|A. Pulmonary alveolar microlithiasis|
Metastatic pulmonary calcification is further subdivided into benign (4–15) and malignant causes (16–21) (Table 1). By far the most common cause of metastatic calcification is seen in patients on hemodialysis for chronic renal insufficiency. The other causes are uncommon (Table 1). Dystrophic calcification follows caseation, necrosis, or fibrosis and may complicate pulmonary infections that include (1) granulomatous infections, for example, Histoplasma capsulatum (22), Coccidioides immitis (23), and Mycobacterium tuberculosis (24); (2) viral infections, for example, varicella virus (25) and smallpox virus (26); and (3) parasitic infections, for example, Paragonimus westermani (27) and Pneumocystis carinii (28) (Table 1). In sarcoidosis, pulmonary calcification can result from either dystrophic calcification or metastatic calcification secondary to hypercalcemia (29, 30). Pulmonary vascular calcification (PVC) is postulated to result from shear stress and is considered to be a variant of dystrophic calcification (31). Dystrophic calcification has also been described in association with amyloidosis and after inhalation exposures in coal workers pneumoconiosis and silicosis. Pulmonary alveolar microlithiasis (PAM) is a unique idiopathic calcific disorder with distinct histologic and radiographic appearances that do not fit into either metastatic or dystrophic calcification (Table 1).
Clinical states that result in both calcium deposition and bone formation are listed in Table 2
I. Idiopathic pulmonary ossification
|II. Preexisting pulmonary disorder|
|A. Idiopathic pulmonary fibrosis|
|B. Pulmonary amyloidosis|
|C. Chronic busulfan therapy|
|D. Acute respiratory distress syndrome|
|E. Hamman-Rich syndrome|
|I. Metastatic breast cancer|
|J. Pulmonary metastases of osteogenic sarcoma|
|K. Metastatic melanoma|
|III. Preexisting cardiac disorder|
|A. Mitral stenosis|
|B. Chronic left ventricular failure|
|C. Idiopathic hypertrophic subaortic stenosis|
|IV. Preexisting extracardiopulmonary disorder|
|A. Primary and secondary hyperparathyroidism|
|B. Hypervitaminosis D|
|C. Pyloric stenosis with alkalosis|
The mechanism(s) of lung calcification with or without ossification is not precisely known. No single factor is responsible. Figure 1Ashows the factors that may be responsible for metastatic calcification in the lungs. Ectopic metastatic calcification can be influenced by serum calcium and phosphate concentration, alkaline phosphatase activity, and local physicochemical conditions such as pH. On the other hand, dystrophic calcification, by definition, requires injured tissues for calcification to occur (discussed later here). For ossification, other influences such as angiogenesis, chronic venous congestion, lung fibrosis, and/or the influence of various growth factors are thought to be necessary (Figure 1B).
Two physiologic requirements for metastatic calcium deposition are the release of excess calcium salts from bone and their transport through the circulation (10). The inorganic component of bone is comprised of apatite minerals with the chemical formula Ca3(PO4)2 · CaX2 where X2 may represent carbonate (CO3), difluoride (F2), dihydroxide ([OH]2), oxygen atom (O), or sulfate (SO4). For conditions that promote calcium release from bone, such as an elevated hydrogen ion concentration, the liberated Ca3(PO4)2 and CaCO3 salts are transported via the blood in soluble form. This is primarily as calcium hypophosphate (CaHPO4), which then reprecipitates as Ca3(PO4)2 and CaCO3 salts in tissues that have a favorable physicochemical environment such as an alkaline pH and a propitious chemical stoichiometry (10).
Although metastatic calcification occurs with normal or even low serum calcium levels, an elevated calcium–phosphate product of more than 70 mg2/dL2 (normal product is approximately 40 mg2/dL2) favors this process (18, 32). Pulmonary metastatic calcification has been identified in patients who succumbed to severe systemic calcinosis from fulminant hyperparathyroid crisis (33–35). There are, however, a few studies that have not supported a correlation between metastatic calcification and the level of the calcium–phosphate ion product (5, 36–38). In cases of metastatic calcification with a normal calcium–phosphate product, it has been hypothesized that previous or current azotemia, an elevated parathyroid hormone, and/or exogenous vitamin D “sensitize” the tissues (Figure 1A). This proposes that previous priming with a calcifying factor, followed by exposure to a challenging agent (e.g., calcium salts, tissue injury, or physical stress), is the basis for pulmonary calcification (39). This hypothesis is supported by a dog model of chronic renal failure (CRF) in which the parathyroid hormone and calcium content of the lungs were increased in the CRF dogs with intact parathyroid glands but not in parathyroidectomized animals (40). Moreover, those with intact parathyroid glands had pulmonary hypertension, supporting the functional relevance of metastatic lung calcification.
Pulmonary parenchymal granulomas and mediastinal and hilar lymphadenopathy associated with fungal diseases, tuberculosis, and sarcoidosis may calcify even in the face of normal serum calcium levels. Although this dystrophic calcification occurs in injured and abnormal tissues, macrophages within granulomas may also produce 1,25 vitamin D, thereby increasing intestinal absorption of calcium and phosphate and providing an additive or synergistic factor that promotes calcification in these tissues (41, 42). This may occur in the absence of detectable increases in serum calcium levels, similar to the ability of supplemental vitamin D and calcium to increase bone density without necessarily raising serum calcium levels.
Calcium salts precipitate in an alkaline environment. In vitro, the usefulness of the calcium–phosphate product in predicting metastatic calcification is compromised in solutions that deviate in either direction from a pH of 7.3. Although impractical in the clinical setting, the calcium–HPO4−2 product is a more accurate predictor of the risk for calcification because it varies with the pH. For example, for a calcium–phosphate product of 44, the calcium–HPO4−2 product is 2.9 × 10−6 in a pH of 3.5 and 2.1 × 10−6 in a pH of 6.8 (43). Thus, in a more alkaline environment, the critical calcium–phosphate product that results in calcium salt precipitation is lower, and conversely, in a more acidic milieu, the calcium–phosphate product that results in calcification is higher (43). This hypothesis gains support from the observation that organs susceptible to metastatic calcification, such as the stomach, kidneys, and lungs, secrete free hydrogen ions, creating an alkaline tissue environment (10, 44). Because the serum is normally saturated with respect to CaHPO4 and an alkaline pH favors retention of this compound, the following reactions could account for the increased delivery and precipitation of Ca3(PO4)2 and CaCO3 in soft tissues with alkalinity (10):
In this regard, it is interesting to speculate that the pH of the blood in the lung is more alkalotic compared with other organs because of CO2 removal. Furthermore, it has been suggested that the upper lobe predilection of some pulmonary calcific disorders is explained by a higher blood pH (approximately 7.51) and lower PaCO2 (approximately 30 mm Hg) at the apex compared with the relatively lower pH at the base (Figure 2)(45). This difference is accounted for by the higher ventilation–perfusion ratio at the lung apex (ventilation–perfusion ratio approximately 3.3) compared with the base (ventilation–perfusion ratio approximately 0.63) (46). That a relatively alkaline pH in the upper lung fields may play a role in the pathogenesis of metastatic calcification was inferred by the findings of a patient with Hodgkin's disease, in whom 99mTc-polyphosphate bone scintigraphy revealed dense accumulation of the radioactive tracer in both upper lung fields (47) and of patients with CRF in whom metastatic calcification occurs commonly in the lung apices (48–50). Further evidence that an alkaline environment fosters calcium precipitation is demonstrated by a patient with the milk–alkali syndrome who developed intra-alveolar microlithiasis (51). The patient, a heavy smoker, had severe metabolic alkalosis and mild hypercalcemia from ingestion of excess quantities of bicarbonate and calcium. Pathologic examination revealed pulmonary microliths that were smaller, more irregular in shape, and not as concentrically laminated as those described with (idiopathic) PAM. Mineralization occurred around nidi of desquamated intra-alveolar cells, the latter possibly related to tobacco use. This case of secondary intra-alveolar microlithiasis was unusual in that hypercalcemia and alkalosis, two conditions predisposing to ectopic calcification, typically cause alveolar septal wall calcification rather than intra-alveolar microlithiasis. Given that calcification is not particularly common in patients with either hypercalcemia or alkalosis alone, alkalosis may, synergistically, predispose to ectopic calcification when other risk factors are present. Using similar logic, metastatic pulmonary calcification in CRF has been linked to the relative alkalosis which follows hemodialysis (5).
Cessation of pulmonary blood flow can lead to pulmonary calcification (37, 52). This has also been partially attributed to tissue alkalosis. Bloodworth and Tomashefski described seven patients with localized pulmonary calcification distal to pulmonary artery obstruction from thrombus or intra-arterial tumor (37). This calcification did not require co-existing infarction, pneumonia, or diffuse alveolar damage. They suggested that obstruction of blood flow to a segment of lung resulted in decreased CO2 delivery, and this, in association with hyperventilation resulting from the vascular occlusion, lowered the alveolar Pco2, causing tissue alkalosis and setting the stage for calcium salt deposition.
Because several isoforms of alkaline phosphatase, an enzyme that elevates the calcium–phosphate product by catalyzing the production of free phosphate, exhibit optimum activity at an alkaline pH (53), alkalosis may in addition predispose to ectopic calcification by this mechanism (Figure 1A). Alkaline phosphatase also enhances osteoblastic activity and thus may be necessary for pulmonary ossification to occur (Figure 1B). Although the presence of elevated alkaline phosphatase and phosphate levels has not been systematically evaluated in pulmonary calcification or ossification, these compounds are increased in the heterotopic ossification of joints secondary to spinal cord injury (54). Present in practically all tissues, alkaline phosphatase is abundantly expressed by alveolar type II cells and nonciliated bronchiolar (Clara) cells (55). Gomori showed that phosphatase activity colocalized with pathological calcification, suggesting that alkaline phosphatases may indeed play an active role in soft tissue calcification and ossification (56). However, this does not explain why calcification fails to occur in healthy tissues normally rich in alkaline phosphatase, such as the kidney and intestinal mucosa (57). Perhaps other factors, such as a local increase in free calcium ions in injured tissues, lower the threshold for calcification.
In contrast to metastatic calcification, dystrophic pulmonary calcification occurs in sites of previous cellular and tissue injury. Calcium is an important ion for cellular integrity, and an increase in intracellular calcium may contribute to the injury. For example, cell necrosis occurring from oxidant injury and inflammation is due, in part, to an increase in free cytosolic calcium. This increase results from a net influx of extracellular calcium across the plasma membrane and the release of intracellular calcium from mitochondria and the endoplasmic reticulum (58) (Figure 3). The elevated intracellular calcium activates a number of enzymes, including phospholipases, proteases, ATPases, and endonucleases, which promote necrotic cell death. In addition, there is leakage of cellular phospholipases into the extracellular space with entry of extracellular phospholipids into the dying cells. Degradation of phospholipids into fatty acids, followed by binding of calcium to the fatty acids, is the hypothesized mechanism for dystrophic calcification at injury sites. This “initiation phase” of dystrophic calcification is followed by a “propagation phase,” with further calcium and phosphate crystallization at the initial nidi of calcification. During cell injury, there is an early fall in pH, followed by a shift to a neutral or alkaline pH as injury continues, the latter state further predisposing to ectopic calcification (58). The calcium-binding phosphoprotein osteopontin appears to play a role in dystrophic calcification. Furthermore, the presence of collagen also enhances the rate of crystal growth. This may be the mechanism by which calcification and subsequent ossification occur in the diffuse pulmonary fibrotic disorders (Figure 1B). Another potential mechanistic link between ossification and pulmonary fibrosis is the ability of the profibrogenic cytokine IL-4 to affect differentiation of macrophages into osteoclasts, the latter required for bone remodeling and absorption (59).
Accelerated respiratory failure caused by extensive calcification of the alveolar septae has been seen (5, 60, 61). Two patients with hypercalcemia, one caused by B-cell lymphoma and the other caused by multiple myeloma, developed fatal acute respiratory distress syndrome (61). Autopsy revealed widespread calcification in addition to the diffuse alveolar damage. Although chronic hyalinized intra-alveolar exudate may become fibrotic and calcify (61), the calcification in these patients was disseminated and their demise rapid, making it less likely that the acute respiratory distress syndrome per se predisposed to the calcification. Instead, it is more likely that the metastatic calcification predisposed to the lung injury by disrupting the normal alveolar–capillary wall or, alternatively, the two processes were independent events.
In the context of bone formation, angiogenesis and osteogenesis are mutually dependent (62). Angiogenesis is a critical process in normal osteogenesis and also may be central to ossification in the lungs. For ossification of injured soft tissues, there is a sequential transformation of fibroblasts first to chondroblasts and then to osteoblasts. This transformation occurs in the presence of both venous stasis and arteriovenous shunting (63). The role of angiogenesis in pulmonary calcification is less clear. Some potential pathophysiologic links between angiogenesis and osteogenesis include the following: (1) osteogenic protein-1, a bone growth factor that upregulates alkaline phosphatase activity and osteoblastic cell differentiation, also enhances the synthesis of vascular endothelial growth factor, a potent angiogenic growth factor for osteoblasts (62). Conversely, disruption of vascular endothelial growth factor synthesis or function inhibits osteogenic protein-1–induced alkaline phosphatase activity and bone formation. (2) Parathyroid hormone, elevated in certain pulmonary calcific disorders, also stimulates vascular endothelial growth factor mRNA expression (64). (3) Prostaglandin E1 and prostaglandin E2, potent stimulators of bone formation in vivo, promote vascular endothelial growth factor production (65); and (4) other angiogenic factors important for bone formation under hormonal control including endothelial cell stimulation angiogenic factor and other novel molecules seem to play a role (66–68). Despite the strong association between angiogenesis and physiologic ossification, the role of angiogenic factors in pulmonary ossification and metastatic or dystrophic pulmonary calcification is yet to be determined.
The extent of physiologic impairment associated with calcium deposition does not necessarily correlate with the degree of macroscopic calcification; that is, some patients with extensive calcification may be asymptomatic, whereas others with more subtle calcification in the face of normal chest radiographs may have significant physiologic impairment. High-resolution computer tomography (HRCT) scan and 99mtechnetium-methylene diphosphate (99mTc-MDP) bone scintigraphy are more sensitive and specific than the chest X-ray for the detection of pulmonary calcification. Their main use is the early recognition of lung calcification or ossification in at-risk individuals, thereby precluding the necessity for surgical lung biopsy to identify unexplained chronic pulmonary infiltrates.
The chest radiograph is useful for the detection of pleural calcification, hilar-mediastinal lymph node calcification, calcified lung nodules, and with less sensitivity, diffuse parenchymal calcification. Even when seen on chest radiograph, diffuse calcification is often mistaken for another process such as pulmonary edema or intrapulmonary hemorrhage, as it appears as nondiscrete infiltrates (33). Similarly, localized pulmonary calcification is often confused with infarction, pneumonia, or malignancy (8, 32, 48, 69–71). In patients in whom there is an increased risk for metastatic calcification, additional studies are usually required, particularly in those with radiographically stable pulmonary opacities.
Three nonmutually exclusive patterns of pulmonary parenchymal calcification may be seen by HRCT scan (Figure 4): (1) multiple calcified and/or apparently noncalcified nodules distributed diffusely or more localized to the certain regions, (2) diffuse or patchy areas of ground glass opacification or ill-defined patchy infiltrate, and (3) a relatively dense area(s) of consolidation that mimics a lobar community acquired pneumonia (44, 50, 72, 73). Moreover, calcification of the tracheobronchial walls and in chest wall blood vessels may be seen (Figure 4). A “ring” pattern of nodular calcification was also described with metastatic calcification secondary to chronic renal disease (50). In seven patients with metastatic pulmonary calcification from different causes, four caused by CRF, the CT scan showed an upper lung zone distribution in three, a diffuse pattern in three, and a predominantly lower lung zone distribution in one (72). Although it has been hypothesized that a higher pH in the lung apices predisposes to metastatic calcification in the upper lobes, there are no rigorous studies that document this. There are cases, such as those described previously here (72) and the case in Figure 5 , that show that metastatic calcification may be more evenly distributed or predominantly in the lower lung zones. To confirm metastatic calcification on CT scan, 1-mm (HRCT) images of the mediastinal windows with or without densitometry measurements should be performed (74). This reveals the high-attenuation characteristic of calcified tissues (44). Although a Hounsfield unit value of greater than 100 in the lung parenchyma may indicate calcified densities, due to signal averaging, an area with less than 100 Hounsfield units does not necessarily exclude parenchymal calcification. Moreover, if the calcification is microscopic, mediastinal CT images may not reveal the calcific densities, especially when standard 7- or 10-mm thick images are obtained. As shown in Figure 5A, only subtle abnormalities are seen on the chest radiograph of a dialysis patient whose biopsy confirms metastatic pulmonary calcification admixed with marked interstitial inflammation (Figure 6) . Although diffuse ill-defined nodular infiltrates were seen on the lung window non-HRCT images (Figure 5B), the mediastinal windows showed no visible calcified lesions (Figure 5C). This lack of confirmation by CT is likely due to the microscopic size of the calcium salt crystals, signal averaging from a relatively large soft tissue component, and the failure to obtain HRCT images.
In a CRF patient with bilateral upper lobe metastatic calcification, lung magnetic resonance imaging revealed nodular lesions with a higher lesion to skeletal muscle signal intensity ratio on T1-weighted imaging than on the T2-weighted imaging (75). However, magnetic resonance imaging is relatively insensitive for detecting pulmonary calcification and is not recommended. The spatial resolution of magnetic resonance imaging is low in the lungs, and in addition, neither calcium nor air in the lung typically transmits a signal, thereby failing to produce a contrast.
Because pulmonary calcification is often misinterpreted as pneumonia or pulmonary edema both on the chest radiograph and CT scan, bone scintigraphy with the bone-avid radiotracer 99mTc-MDP helps sort out equivocal cases (16, 48, 76–78). Figure 7shows the bone scintigraphy in a patient with CRF demonstrating increase uptake in both lungs (right > left) as well as intense gastric uptake. The simultaneous uptake of 99mTc-MDP in the lungs and stomach was previously described in a CRF patient and in a patient with acute fulminant hyperparathyroidism (79, 80). Moreover, for reasons unknown, 67gallium citrate scintigraphy only detected the lung focus (80). Although other reports indicate increased 67gallium citrate pulmonary uptake in metastatic calcification (81), it is not a uniform finding (82). Coolens and colleagues described 24 patients with positive pulmonary bone scintigraphy and hypercalcemia caused by hyperparathyroidism but without chest radiographic evidence of calcification (83). Seven autopsied cases had extensive calcifications within the alveolar walls and pulmonary vessels, confirming the greater sensitivity of bone scintigraphy for detecting pulmonary calcification.
It has been proposed that in uremia, 99mTc-MDP scintigraphy has a lower sensitivity for detecting pulmonary calcification when compared with hyperparathyroidism or malignancy (84). This difference is perhaps due to the relatively lower uptake of 99mTc-MDP by amorphous whitlockite type mineral ([CaMg]3[PO4]2) compared with hydroxyapatite crystals (Ca10[PO4]6[OH]2), the former being the predominant calcium salt in renal failure-associated metastatic calcification (84). Nevertheless, in 23 patients receiving maintenance hemodialysis but without evidence of pulmonary calcification on chest radiograph, 14 (61%) were prospectively found to have a positive 99mTc-MDP bone scan of the lungs. The only distinguishing clinical feature in those with a positive scan was a longer duration of hemodialysis (38 ± 5 months) than for those with negative scans (12 ± 4 months) (85).
The standard chest roentgenogram is relatively insensitive for the detection of diffuse pulmonary calcification with or without ossification. Typically, the study is negative or the infiltrates cannot be distinguished from other parenchymal processes. Exceptions are large and densely calcified parenchymal nodules, lymph nodes, or pleura. HRCT mediastinal images and 99mTc-MDP bone scintigraphy are relatively specific for pulmonary calcification and ossification. There are, however, two important caveats concerning the CT diagnosis of ectopic calcification and ossification: (1) The presence of dense lesions on lung window images will not distinguish between noncalcified and calcified opacities and conversely, (2) because of signal averaging, the failure to detect calcification or ossification on mediastinal images does not unequivocably exclude the possibility if the calcified lesions are microscopic, if there is a relatively large soft tissue component, and/or if standard 10-mm slices are imaged. Although bone scintigraphy appears to be more sensitive than CT scans in detecting ectopic calcification and ossification, this observation is based on anecdotal case reports without prospective comparison studies. One advantage of the CT scan is that the thorax and lung parenchyma can also be evaluated in detail. The advantage of scintigraphy is that other organs can be concurrently evaluated for metastatic calcification or ossification.
In this section, we discuss in greater depth specific disorders of pulmonary calcification and ossification that illustrate the mechanistic principles and imaging features described in the previous sections.
In this subsection, we highlight those conditions associated with metastatic calcification for which some pathophysiologic explanation exists, although much remains unknown. Metastatic pulmonary calcification is associated with a variety of benign and malignant disorders (Table 1). The prevalence in an unselected population is relatively low. In a retrospective review of over 7,000 autopsies, only 14 cases of metastatic calcification were identified: three with CRF, seven associated with tumor-induced bone destruction, and four with hyperparathyroidism (86). In contrast, metastatic pulmonary calcification was found in 60–75% of hemodialyzed patients at autopsy (5, 38). Conger and colleagues prospectively studied pulmonary calcification in chronically hemodialyzed patients who subsequently died (5). In the nine with lung parenchymal calcification, only one had premorbid chest radiographic evidence of pulmonary infiltrates. The calcium deposits were located in the alveolar epithelial basement membranes, the alveolar capillary walls, the bronchial walls, and the media of pulmonary arterioles. Figure 6 demonstrates the histopathologic features of diffuse metastatic pulmonary calcification in a CRF–hemodialysis patient. As seen in the figure, there is an associated interstitial fibroproliferative response, leading to further restrictive physiology (38, 87, 88). Calcium phosphate represents the principal mineral salt of CRF-associated metastatic calcification, which is similar to the composition of normal bone or dystrophic calcification (89). X-ray diffraction analysis indicates that the predominant crystal configuration is whitlockite with a smaller amount of calcium pyrophosphate (CaP2O7). The whitlockite pattern of CRF-associated metastatic pulmonary calcification is distinct from the hydroxyapatite variety, typically found in other forms of pulmonary and soft-tissue metastatic calcifications (84, 90).
In CRF patients undergoing hemodialysis, four conditions predispose to metastatic calcification. First, acidosis leaches calcium and phosphate from bone. Second, there is increased parathyroid hormone secretion caused by a negative calcium balance created by the failure of the kidneys to convert 25 vitamin D to 1,25 vitamin D, resulting in increased calcium and phosphate release from bone. Although patients with this secondary form of hyperparathyroidism are already at risk for metastatic calcification (91, 92), occasionally the stimulated parathyroid gland becomes autonomous, resulting in tertiary hyperparathyroidism and severe hypercalcemia (93). Third, intermittent alkalosis, which often accompanies bicarbonate hemodialysis, predisposes to soft tissue precipitation of calcium salts. This is supported by the observation that metastatic soft tissue calcification is accelerated following hemodialysis (5, 38, 94). Finally, the decreased glomerular filtration of phosphate may contribute to an elevated serum calcium–phosphate product. Elevated serum phosphate levels have been shown to correlate highly with vascular calcification in uremic patients (95). This observation was experimentally confirmed in cultured human aortic smooth muscle cells in which media containing phosphate levels comparable to those seen in hyperphosphatemic patients showed dose-dependent increases in cell culture calcium deposition (95). In contrast to the relatively physiologically benign course of pulmonary calcification in most patients, severe cases have been described (5, 70, 88, 96, 97). For example, in a patient with long-standing renal insufficiency and nephrotic syndrome, widespread metastatic calcification of multiple organs occurred after 3 months of bicarbonate hemodialysis (94). Although the calcium–phosphate product was normal, the free calcium index was elevated because of depressed serum protein, leading to ectopic calcium–phosphate deposition.
In 91 patients who underwent orthotopic liver transplantation, chest radiographs, despite their relative insensitivity, detected pulmonary calcification in 5.2% (8). The mechanism is unclear. Complicating renal failure, acid-base abnormalities, and the administration of exogenous calcium and citrate have been proposed as contributing events. Elevated plasma citrate concentrations caused by the administration of packed red blood cells could lead to metabolic alkalosis and calcium chelation, prompting parathyroid release of parathyroid hormone. This gains support from the observation that the patients with calcification had higher levels of phosphorus and calcium postoperatively and had received more intraoperative blood products, all containing exogenous calcium (8).
Although metastatic calcification most often accompanies a benign systemic metabolic disorder, it may also be associated with a variety of malignancies in which a common pathophysiologic attribute is the presence of hypercalcemia and/or an elevated calcium–phosphate product (Table 1) (98). Here the hypercalcemia may either be hormonally mediated or may result from metastasis to bone. Metastatic calcification is rare, however, even for these malignancies. In the case of osteogenic sarcoma, the ectopic calcification is secondary to the metastatic tumor itself.
The clinical importance of metastatic calcification in slowly progressive cases is the confusion it creates in the evaluation of an abnormal chest radiograph in patients at risk for this process, particularly those undergoing hemodialysis or individuals with elevated calcium–phosphate product. In extensive pulmonary calcification, a restrictive physiology, a decreased diffusion capacity, and hypoxemia result (33). Rarely, progressive respiratory insufficiency and death may ensue (9, 99). 99mTc-MDP scintigraphy or mediastinal images on HRCT scan may be diagnostic of metastatic calcification without need for further investigation. The Von Kossa stain is significantly more sensitive than the standard hematoxylin and eosin stain in detecting calcium in tissues (100). Electron microscopy is even more sensitive and can show specific intracellular and extracellular sites of calcification, although it is not generally clinically available (101). Specific treatment is aimed at correction of isolated hyperphosphatemia or elevated calcium–phosphate product, if present. Successful renal transplantation may ameliorate metastatic pulmonary calcification (91), and conversely, renal graft failure and persistent uremia may accelerate, by some unexplained mechanism, the ectopic calcification (102). Moreover, metastatic pulmonary calcification may inexplicably progress despite a normally functioning renal allograft and normal or near-normal calcium and phosphate levels, although occult tertiary hyperparathyroidism may be responsible for some of these rare cases (96, 97). In severe recalcitrant cases associated with primary or tertiary hyperparathyroidism, parathyroidectomy is indicated (96).
Microbial infections that elicit a granulomatous tissue response can also result in a variety of thoracic dystrophic calcifications (Table 1). H. capsulatum–related thoracic calcifications include calcified mediastinal lymph nodes/broncholithiasis, mediastinal granuloma, and solitary or multiple calcified histoplasmomas (103, 104). In addition to single or several large histoplasmomas, there may be numerous, small, diffuse, calcified pulmonary nodules in asymptomatic patients (Figure 8A). Although the lung window image of the chest CT also showed the dense nodules (Figure 8B), the mediastinal image showed a paucity of calcified lesions (Figure 8C), due to the signal averaging effect obtained with 10-mm slices. This pattern of calcification likely results from either hematogenous or bronchogenic dissemination of this granulomatous infection (105). Although hypercalcemia caused by chronic granulomatous infections occurs, it is unusual. Nevertheless, nontoxic supplemental doses of vitamin D have been reported to exacerbate the hypercalcemia of tuberculosis, sarcoidosis, and histoplasmosis (106–108), which may further predispose to the dystrophic calcification seen.
Pulmonary calcification as a sequela of C. immitis infection is uncommon (109). However, regressive changes of coccidioidal pulmonary lesions may result in single or multiple dystrophic calcified nodules.
Tuberculosis produces a number of chest calcifications. Dystrophic calcification may manifest in parenchymal granulomas, mediastinal lymph nodes, and fibronodular areas of lung involvement. Diffuse nodular calcification of the lungs may follow treatment of a hematogenous infection (24). Roussos and coworkers recently showed that patients with tuberculosis can develop hypercalcemia caused by excessive production of endogenous 1,25 vitamin D, thus further predisposing to dystrophic pulmonary calcification (110). In a rabbit model of tuberculosis, early granulomatous inflammation without necrosis lacked phosphatase activity (56). However, when caseous necrosis occurred, there was robust phosphatase activity within the necrotic centers. Subsequent calcification was invariably found in the phosphatase-positive areas. Clinically, tuberculous calcification enhances tissue friability at surgery but is generally inconsequential and does not affect mortality.
In unusual instances, sarcoidosis may produce multiple micronodular calcifications, radiographically similar to PAM (111). In contrast, however, their histologic features are distinct: In sarcoidosis, calcification is confined to the epitheloid granulomas, and in PAM, there are distinct intra-alveolar microliths.
Although less than 5% of chickenpox cases occur in adults, adult infections are associated with a higher incidence of pneumonic complications. Radiographically, varicella pneumonia typically shows scattered ill-defined nodular or reticular densities. The infiltrates usually resolve over time, but in some cases, asymptomatic miliary calcifications appear 3 to 5 years following the acute event (Figure 9)(112, 113).
Late development of pulmonary calcification from previous smallpox virus exposure has also been illustrated (26, 114). In nurses who developed flu-like illnesses within days of exposure to a smallpox patient, radiographic studies often showed poorly defined nodular opacities, attributed to a modified variola pneumonia. After clinical resolution of the acute illness, follow-up chest radiographs revealed extensive well-defined punctate calcifications without physiologic abnormalities (26). Other DNA viruses such as herpes simplex have been reported to lead to calcification (115). In an infant who died from presumptive herpes simplex pneumonia, the alveolar septae were extensively calcified (112). This case was unusual because fulminant calcification complicated the acute phase of the disease.
Pulmonary and thoracic lymph node calcifications associated with P. carinii infection, with or without concomitant human immunodeficiency virus infection, have been described, albeit uncommonly (116–119). Widespread visceral calcification has also been reported in disseminated pneumocystosis (120, 121). In some cases, the pulmonary and extrapulmonary calcification was associated with a granulomatous response to the infection (28, 116, 117, 119, 120). In a human immunodeficiency virus–positive individual receiving aerosolized pentamidine, extensive upper lobe calcification was observed (122). However, in contrast to the upper lobe distribution, which occurs in some cases of metastatic calcification, this was likely due to the suboptimal delivery of aerosolized pentamidine to the upper lobes. In a detailed pathologic study of 13 cases of pneumocystosis-associated pulmonary calcification, various calcification patterns were seen, the most common being a “bubbly” appearance in which aggregates of punctate calcification were admixed with P. carinii cysts (28). An important diagnostic pearl is that this pattern was not associated with the typical intra-alveolar foamy exudate seen with active pneumocystosis. Both parenchymal and pleural calcification can also occur with P. westermani pulmonary infection and are thought to be related to the calcified mummification of the parasite (27).
Primary amyloidosis results from the abnormal production and tissue deposition of light chain (AL) protein, derived from the variable portion of the immunoglobulin light chain. Because amyloid fibrils have an affinity for calcium, secondary calcification can occur in amyloidosis (123). The lungs are affected in up to half of patients with primary amyloidosis, appearing as either localized or diffuse disease of the airways or lung parenchyma (124, 125). The calcified lung lesions associated with diffuse parenchymal amyloidosis are typically characterized radiographically by interstitial or mixed interstitial-alveolar infiltrates, admixed with varying degrees of calcification—rarely ossification—and located predominantly in the subpleural regions of the mid and lower lung zones (126) (Figures 10A and 10B). The appearance of calcification in amyloidosis is unusual, but its presence is often the first indication of primary amyloidosis.
Detectable PVCs, although uncommon, usually indicate a significant underlying chronic condition. Because PVCs occur in areas of high flow, they are detected in larger vessels (31). However, little is known about their pathogenesis. Similar to the evolving knowledge of the pathogenesis of calcification in the pulmonary parenchyma, there are parallel advances in understanding regulation of vascular calcification.
Atherosclerosis is unusual in the pulmonary circulation, where the mean arterial pressures are significantly lower than in the systemic circulation (127). For atherosclerosis to occur in the pulmonary circulation, it appears to require both an increase of the mean arterial pressure and a pathologic state, which produces high flow. Atherosclerosis may be seen in long-standing pulmonary hypertension in patients with primary pulmonary hypertension (128–130) and those with congenital heart disease (127).
Although there is little direct investigation on the cell biology of PVC, parallels between PVC and systemic arterial calcification can be made. In atherosclerotic systemic vessels, calcium deposits and lamellar bone form at the intimal medial interface or within the media of the blood vessel (131). Using in situ hybridization, bone morphogenic protein-2, an osteogenic differentiation factor, is expressed in the calcified vascular lesions (Figure 1B) (131). Pericytes, cells that surround pulmonary vessels and are instrumental in regulating angiogenesis, can differentiate into osteogenic cell lines (132). Thus, they have the potential to orchestrate calcification or bone formation in the pulmonary vasculature. Vascular endothelial growth factor, a potent mitogen involved in the hypoxic vascular response, is one potential link between hypertensive remodeling with calcification or ossification (see The Role of Angiogenesis in Proposed Mechanisms of Ectopic Lung Calcification and Ossification and Figure 1) (133). Further investigation of PVC could provide insights into the role of physical stresses such as high wall shear stress in the modulation of growth factors that redirect differentiated cells into an osteogenic program.
Conditions producing increased vascular wall shear stress or high flow are presumed to be important for the formation of dystrophic PVC for the following reasons: (1) There is an increased susceptibility of vascular grafts to calcification (134). (2) There are PVCs in clinical states associated with increases in either vessel wall shear stress or increased pulmonary blood flow and pulmonary hypertension, and (3) in utero development of PVC with severe volume overload has been seen (135).
High wall shear stress, the presumed pathogenetic condition that most often leads to calcification, accompanies vascular grafting in the pulmonary circulation. In children with cyanotic congenital heart disease who underwent a modified Blalock-Taussig shunt procedure with placement of vascular grafts, graft removal years later demonstrated areas of active angiogenesis and adjacent graft calcification (134). Sites of pulmonary artery contact with saphenous vein grafts used for coronary artery bypass demonstrate pulmonary artery calcification visible on CT scan (136). Although the mechanisms of graft calcification are unknown, the application of heparin on prosthetic vascular grafts, including pulmonary artery grafts, diminishes calcification, suggesting a role for coagulation (137).
High shear forces and calcification also occur in pulmonary hypertension most often as the result of congenital heart disease. Early reports of pulmonary artery calcification described radiographic calcification in the main pulmonary arteries or large branch vessels in severe long-standing pulmonary hypertension with elevated pulmonary vascular resistance and a right to left shunt (Eisenmenger's syndrome) (138). Pulmonary artery calcification has also been reported in a left to right shunt from patent ductus arteriosis and long-standing ventricular and atrial septal defects (138–141).
In in utero twins with a common heart and high-flow and volume overload, pulmonary artery calcifications were present in the large vessels adjacent to the functioning heart (135). Histologically, there was hyperplasia of the intimal and medial layers and disruption and calcification of the medial elastic fibers. This appearance is similar to that described in the autosomal recessive disorder of idiopathic arterial calcification of infancy (142). Calcification may also occur with pulmonary venous hypertension and hemosiderosis, particularly in the setting of long-standing mitral stenosis (130). Idiopathic pulmonary hemosiderosis has also been associated with calcification of the elastic lamina of pulmonary arteries, arterioles, and veins (130), possibly through a combination of hemorrhage-induced inflammation with or without increased shear stress.
PVC occurs as a result of high shear stress of long duration. The role of injury and inflammation and accompanying angiogenesis and vascular smooth muscle cell reprogramming to an “embryonic osteogenic program” is of possible importance. Recent work suggests that calcification of the medial layer in systemic vessels from end-stage renal disease patients is associated with increased bone morphogenic protein and alkaline phosphatase activity, potentially linking the metastatic calcification process to vascular calcification as well (143). The major clinical importance of finding PVC is the implication of the chronicity and severity of the underlying condition.
PAM, a rare disorder of unknown etiology, is recognized by the intra-alveolar accumulation of spherical calcified concretions (144). Most patients are between 30 and 50 years of age when first discovered. Although there is a familial association in at least 50% of the cases, common environmental factors could also account for this observation (145, 146). This disease is especially prevalent in Turkey, representing 33% of the world literature (147), although reporting bias cannot be totally excluded. There is no evidence that infection plays a role. An isolated inborn error of calcium metabolism in the lungs has been proposed, but circulating calcium and phosphorus levels are consistently normal in PAM. It is speculated that, due to an unknown stimulus, changes in the alveolar lining membrane or secretions result in greater alkalinity, promoting intra-alveolar precipitation of calcium phosphates and carbonates (148). Coetzee described a patient with PAM, with similar pathologic and radiographic findings in the lumbar sympathetic chains and testes, suggesting that PAM was a systemic disorder in this individual (145).
Asymptomatic cases, even with extensive radiographic involvement, are often discovered incidentally. Cough and dyspnea are the most common presenting symptoms and usually occur late in the course of the disease. Normal or mild restrictive pulmonary physiology may be present in the asymptomatic individual. With progressive disease, severe lung restriction may ensue with impairment of the diffusing capacity and gas exchange abnormalities. The chest radiograph shows bilateral, sand-like, micronodular calcified densities known as microliths or calcispherites, which are usually less than 1 mm in diameter (149). They appear concentrated in the lower two-thirds of the lung, often obliterating the diaphragmatic, mediastinal, and cardiac borders (Figure 11). The greater radiographic density at the lung bases is likely due to the larger lower lobe volumes rather than selective predisposition. The predominant HRCT finding is the presence of micronodular calcifications primarily located along the bronchovascular bundles, subpleural regions, and perilobular distribution (149). HRCT may in addition reveal ground glass opacities that are interspersed with microcysts and the calcispherites (149). In addition to the fine nodulation, HRCT may show polygonal-shaped calcified densities caused by the accumulation of microliths in the periphery of the lobules rather than to actual thickening or to deposition of calcium within alveolar septae (149, 150). Although 99mTc-bone scintigraphy can also help confirm the calcific nature of the lesions, the standard chest radiograph is often characteristic for PAM. Identification of microliths in expectorated sputum or bronchoalveolar lavage is diagnostic. Histologically, the lesion of PAM consists of intra-alveolar calcispherites, which represent laminated calcium phosphate concretions (Figure 12) . This appearance is distinct from metastatic and dystrophic calcifications in which the calcification is in the interstitial or vascular compartments. With progression, interstitial inflammation and fibrosis will occur and result in significantly diminished lung volumes, sometimes finger clubbing and eventually right heart failure. There is no known therapy for PAM. Corticosteroids, chelating agents, and bronchoalveolar lavage have demonstrated no benefit, and the role for the use of bisphosphonates remains to be proven (151). The few cases with response to corticosteroids are more likely to be related to attenuation of the accompanying interstitial disease (152). In symptomatic cases, nasal continuous positive airway pressure improves gas exchange by decreasing the physiologic intrapulmonary shunt (153). Bilateral lung transplantation is a viable option for far advanced cases.
Bone formation with or without marrow components occurring in the interstitial and alveolar compartments is unusual. Pulmonary ossification can be idiopathic or be associated with a variety of underlying pulmonary, cardiac, and systemic disorders (154–160). As can be seen in Table 2, many of the conditions associated with pulmonary ossification also occur with metastatic or dystrophic calcification; thus, ossification could represent a continuation of either process in the lung (161, 162).
The pathogenesis of pulmonary ossification is unknown. Serum calcium and phosphorus levels are usually normal. Unlike heterotopic ossification that occurs around joints in association with spinal cord injuries (54), the serum alkaline phosphatase levels in pulmonary ossification are generally within normal limits, although this has not been consistently evaluated. In cases associated with pulmonary venous congestion, chronic intra-alveolar hemorrhage has been implicated as a predisposing factor for subsequent fibrosis and ossification (163). Ossification is the sequela of a series of events beginning with degeneration of the arterial media, followed by inflammation and hyalinization of the perivascular tissue. Growth factors from cells involved in this extracellular matrix formation and resolution of inflammation may also play a role in ossification (Figure 1). Transforming growth factor-β is elaborated by inflammatory macrophages and damaged epithelial cells and represents a critical growth factor for collagen and the extracellular matrix. Transforming growth factor-β, strongly implicated in idiopathic pulmonary fibrosis and other fibrotic pulmonary diseases (164), also stimulates osteoblast and chondrocyte proliferation. Another growth factor that may play an important role in ectopic pulmonary ossification is bone morphogenic protein, a member of the transforming growth factor-β superfamily (165). Bone morphogenic protein, which is likely important in the development of familial primary pulmonary hypertension (166), induces ectopic bone formation in the rat submandibular gland (167). Interleukin-1 has also been shown to enhance bone morphogenic protein–induced hereotopic ossification in laboratory animals (168). The profibrotic cytokine interleukin-4, in conjunction with monocyte-colony stimulating factor, may also transform human alveolar macrophages to osteoclasts, a cell important in bone remodeling (59). Although the role of fibrogenic, angiogenic, and osteogenic growth factors and cytokines in idiopathic and secondary pulmonary ossification is unexplored, their influence may potentially induce ossification in fibroproliferative pulmonary disorders such as idiopathic pulmonary fibrosis.
Pulmonary ossification has features of both experimentally induced bone formation and embryologic bone development (169). Local ionic charges, inflammation, and tissue anoxia promote the transformation of cultured fibroblasts into osteoblasts (170, 171). Stress forces that normally shape growing bone also stimulate cell proliferation. In an analogous fashion, shear stresses in noncompliant lung tissue due to fibrosis may induce the conversion of fibroblast to osteoblasts and ultimately bone formation (170).
The interstitial deposition of bone can be localized or widely distributed throughout the pulmonary parenchyma. Two histologic types of pulmonary ossification have been described (159): (1) a nodular circumscribed form and (2) a dendriform type. The nodular form is characterized by lamellar deposits of calcified osteoid material situated within the alveolar spaces often without marrow elements (Figure 13A). Although the lesion shown in Figure 13A is from a patient with idiopathic pulmonary ossification (IPO), the nodular form is typically associated with pre-existing cardiac disorders that result in chronic pulmonary venous congestion such as mitral stenosis, chronic left ventricular failure, and idiopathic hypertrophic subaortic stenosis (170, 172–174) (Table 2). In contrast, dendriform ossification refers to interstitial branching spicules of bone and marrow elements that may protrude into the alveoli. The dendriform type is found in IPO (Figures 13B and 13C) and follows interstitial fibrosis (Figure 13D) (159). Based on this simplified morphologic classification for pulmonary ossification, it is interesting to speculate that some cases of IPO may represent a sequela of previously unidentified lung injuries.
IPO most often is found in men over age 60 but also has been reported in younger adults and in women. Patients can be asymptomatic or have minimal complaints, and IPO represents an unexplained radiographic finding. Many cases are diagnosed at autopsy. A restrictive pulmonary physiology with low diffusion capacity is present when disease is extensive (156, 175). In the secondary forms, signs, symptoms, and the physiologic abnormalities are more likely due to the accompanying disorder. It is uncommon for pulmonary ossification to be seen on the chest radiograph. When present, it involves the lower lobes, appearing as nonspecific reticulonodular densities (74) (Figure 14A). On a HRCT scan, linear 1- to 4-mm calcific densities are seen (Figure 14B), and occasionally, punctate, miliary, or small nodular calcifications are visible (74). With thin 1-mm slices of the mediastinal images, the bone density of the lesions is confirmed (Figure 14C). Pulmonary ossification may also be detected by 99mTc-MDP nuclear scans (176, 177). Corticosteroids, calcium-binding drugs, and low-calcium diets have no discernable benefit, although they have not been systematically evaluated; the role of bisphosphonates remains to be determined. Because there is no proven treatment for pulmonary ossification, any therapy directed at the ossification should be considered experimental and reserved only for symptomatic cases.
Pulmonary calcification and ossification are relatively rare and often asymptomatic. Several predisposing conditions are associated with pulmonary parenchymal calcification with or without ossification. These include hypercalcemia, hyperphosphatemia, alkalosis, and lung injury in the presence or absence of conditions that result in angiogenesis and increased pulmonary blood flow causing elevated vessel wall shear stress. The clinical states associated with pulmonary calcification include several major diseases including CRF, orthotopic liver transplantation, granulomatous infection, infection by DNA viruses or parasites, pulmonary amyloidosis, and pulmonary vascular disease; PAM is considered a unique form of ectopic pulmonary calcification. For some conditions, for example, pulmonary fibrosis or PVC, the calcification may be a marker of disease severity and accelerated morbidity. Pulmonary ossification may be idiopathic or may be secondary to fibrotic lung disorders, cardiac diseases that result in pulmonary venous hypertension, or disorders that raise the calcium–phosphate product levels. The pathogenesis of pulmonary ossification may parallel that of PVC with elevations of left atrial pressure and possible high shear stress forces leading to degeneration of the arterial media, although understanding of the pathogenesis is incomplete. Current diagnostic studies may be useful in revealing pulmonary parenchymal calcification. Bone scintigraphy and HRCT scan with mediastinal images are both superior to standard chest radiography in detecting calcification and ossification when these conditions are clinically suspected.
The authors thank Dr. Robert Quaife for the 99mTc-MDP bone scan of the patient with metastatic calcification and are very grateful to Barry Silverstein for expert illustrative assistance.
Supported by grant RO1-HL66112-01A1, a Parke-Davis Atorvastatin Research Award, and the American Lung Association Career Investigator Award (E. C.); a Veterans Affairs Merit Review Award (C. W.); and a National Heart, Lung and Blood Institute–Specialized Center of Research Pulmonary Fibrosis grant HL-67671-01 (M. S.).
|1.||Laennec RTH. De l'auscultation mediate. Paris: J-A Brosson and J-S. Chaude; 1819.|
|2.||Garrison FH. History of medicine with medical chronology, suggestions for study and bibliographic data, 4th ed. Philadelphia: W.B. Saunders; 1929.|
|3.||Brown K, Mund DF, Aberle DR, Batra P, Young DA. Intrathoracic calcifications: radiographic features and differential diagnoses. Radiographics 1994;14:1247–1261.|
|4.||Cohen AM, Maxon HR, Goldsmith RE, Schneider HJ, Wiot JF, Loudon RG, Altemeier WA. Metastatic pulmonary calcification in primary hyperparathyroidism. Arch Intern Med 1977;137:520–522.|
|5.||Conger JD, Hammond WS, Alfrey AC, Contiguglia SR, Stanford RE, Huffer WE. Pulmonary calcification in chronic dialysis patients: clinical and pathologic studies. Ann Intern Med 1975;83:330–336.|
|6.||Gilman M, Nissim J, Terry P, Whelton A. Metastatic pulmonary calcification in the renal transplant recipient. Am Rev Respir Dis 1980;121: 415–419.|
|7.||Justrabo E, Genin R, Rifle G. Pulmonary metastatic calcification with respiratory insufficiency in patients on maintenance haemodialysis. Thorax 1979;34:384–388.|
|8.||Libson E, Wechsler RJ, Steiner RM. Pulmonary calcinosis following orthotopic liver transplantation. J Thorac Imaging 1993;8:305–308.|
|9.||McLachlan MSF, Wallace M, Seneviratne C. Pulmonary calcification in renal failure: report of three cases. Br J Radiol 1978;41:99–106.|
|10.||Mulligan RM. Metastatic calcification. Arch Pathol 1947;43:177–230.|
|11.||Raisis IP, Park CH, Yang SL, Maddrey W. Lung uptake of technetium-99m phosphate compounds after liver transplantation. Clin Nucl Med 1988;13:188–189.|
|12.||Sam JW. Metastatic pulmonary calcification following orthotopic liver transplant. Semin Roentgenol 1999;34:253–255.|
|13.||Wermer P, Kuschner M, Riley EA. Reversible metastatic calcification associated with excessive milk and alkali intake. Am J Med 1953;14: 108–115.|
|14.||Wilson CW, Wingfield WL, Toone EC. Vitamin D poisoning with metastatic calcification. Am J Med 1953;14:116–123.|
|15.||Winter EM, Pollard AJ, Chapman S, Kelly D, Spencer D. Case report: pulmonary calcification after liver transplantation in children. Br J Radiol 1995;68:923–925.|
|16.||Aso Y, Sato A, Tayama K, Takanashi K, Satoh H, Takemura Y. Parathyroid carcinoma with metastatic calcification identified by technetium-99m methylene diphosphonate scintigraphy. Intern Med 1996; 35:392–395.|
|17.||Cohen MC, Drut R. Metastatic pulmonary calcification with ossification in a child with acute lymphoblastic leukemia. Pediatr Pulmonol 1999;27:134–137.|
|18.||Kempter H, Hagner G, Savaser AN, Huben H, Mingguillon C. Metastatic pulmonary calcification in a patient with nonsecretory multiple myeloma. Respiration 1986;49:77–80.|
|19.||McCook TA, Putman CE, Dale JK, Wells SA. Medullary carcinoma of the thyroid: radiographic features of a unique tumor. Am J Roentgenol 1982;139:149–155.|
|20.||Suzuki L, Funari M, de Rocha S, Cristofani LM, Odone-Filho V, Vieira GS. Calcification in primary lung non-Hodgkin lymphoma. Rev Hosp Clin Fac Med Sao Paulo 1995;50:227–229.|
|21.||Weber CK, Friedrich JM, Merkle E, Prummer O, Hoffmeister A, Mattfeldt T, Frickhofen N. Reversible metastatic pulmonary calcification in a patient with multiple myeloma. Ann Hematol 1999;72:329–332.|
|22.||Lace PA. An investigation into the aetiological factors concerned in disseminated calcification of the lungs. Med J Aust 1968;23:951–953.|
|23.||Sargent EN, Balchum E, Freed AL, Jacobson G. Multiple pulmonary calcifications due to coccidioidomycosis. Am J Roentgenol Radium Ther Nucl Med 1970;109:500–504.|
|24.||Katz S, Stanton J, McCormick G. Miliary calcification of the lungs after treated miliary tuberculosis. N Engl J Med 1955;253:135–137.|
|25.||Raider L. Calcification in chickenpox pneumonia. Chest 1971;60:504–507.|
|26.||Ross PJ, Seaton A, Foreman HM, Evans WHM. Pulmonary calcification following smallpox handler's lung. Thorax 1974;29:659–665.|
|27.||Chen SZ. An analysis of radiologic signs of typical pulmonary calcification in 8 cases of paragonimiasis. Zhonghua Fang She Xue Za Zhi 1984;18:128–130.|
|28.||Lee MM, Schinella RA. Pulmonary calcification caused by Pneumocystis carinii pneumonia: a clinicopathological study of 13 cases in acquired immune deficiency syndrome patients. Am J Surg Pathol 1991;15:376–380.|
|29.||Israel HL, Sones M, Roy RL, Stein GN. The occurrence of intrathoracic calcification in sarcoidosis. Am Rev Respir Dis 1961;84:1–11.|
|30.||Rohatgi PK. Metastatic pulmonary calcification in sarcoidosis. Respiration 1988;54:201–205.|
|31.||Mendlowitz M. Arterial calcium metabolism, hypertension, and arteriosclerosis. Cardiology 1981;67:81–89.|
|32.||Neff M, Yakin S, Gupta S, Berger H. Extensive metastatic calcification of the lung in an azotemic patient. Am J Med 1974;56:103–109.|
|33.||Khafif RA, DeLima C, Silverberg A, Frankel R. Calciphylaxis and systemic calcinosis: collective review. Arch Intern Med 1990;150:956–959.|
|34.||Schweitzer VG, Thompson NW, Herness JK, Nishiyama RH. Management of severe hypercalcemia caused by primary hyperparathyroidism. Arch Surg 1978;113:373–381.|
|35.||Wang C, Guyton SW. Hyperparathyroid crisis. Ann Surg 1979;190:782–790.|
|36.||Bein ME, Lee DBN, Mink JH, Dickmeyer J. Unusual case of metastatic pulmonary calcification. AJR Am J Roentgenol 1979;132:812–816.|
|37.||Bloodworth J, Tomashefski JF. Localised pulmonary metastatic calcification associated with pulmonary artery obstruction. Thorax 1992; 47:174–178.|
|38.||Kuzela DC, Huffer WE, Conger JD, Winter SD, Hammond WS. Soft tissue calcification in chronic dialysis patients. Am J Pathol 1977;86: 403–424.|
|39.||Allegra L. Experimental pulmonary calcification. Exp Med Surg 1965; 23:227–238.|
|40.||Akmal M, Barndt RR, Ansari AN, Mohler JG, Massry SG. Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy. Kidney Int 1995;47:158–163.|
|41.||Bell NH, Sharg J, Shaw S, Turner RT. Hypercalcaemia associated with increased circulatory 1,25 dihydroxyvitamin-D in a patient with pulmonary tuberculosis. Calcif Tissue Int 1985;37:588–591.|
|42.||Kerr DNS. Hypercalcemia and metastatic calcification. Cardiovasc Res 1997;36:293–297.|
|43.||Shear MJ, Kramer B. Composition of bone: physicochemical mechanisms. J Biol Chem 1928;79:125–145.|
|44.||Greenberg S, Suster B. Metastatic pulmonary calcification: appearance on high resolution CT. J Comput Assist Tomogr 1994;18:497–499.|
|45.||West JB. Regional differences in blood flow and ventilation in the lung. In: Caro CG, editor. Advances in respiratory physiology. Baltimore: Williams and Wilkins; 1966. p. 198–254.|
|46.||West JB. Respiratory physiology: the essentials, 4th ed. Baltimore: Williams and Wilkins; 1990.|
|47.||Moinuddin M, Rockett JF, Weber A. Scanning for pulmonary calcification. Ann Intern Med 1976;84:224-225.|
|48.||Brodeur FJ, Kazerooni EA. Metastatic pulmonary calcification mimicking air-space disease: technetium-99m-MDP SPECT imaging. Chest 1994;106:620–622.|
|49.||Jost RG, Sagel SS. Metastatic calcification in the lung apex. AJR Am J Roentgenol 1979;133:1188–1190.|
|50.||Lingam RK, Teh J, Sharma A, Friedman E. Metastatic pulmonary calcification in renal failure: a new HRCT pattern. Br J Radiol 2002; 75:74–77.|
|51.||Portnoy LM, Amadeo B, Hennigar GR. Pulmonary alveolar microlithiasis: an unusual case associated with milk-alkali syndrome. Am J Clin Pathol 1964;41:194–201.|
|52.||Wraight EP. Focal lung uptake of technetium 99m methylene diphosphate associated with pulmonary emboli and hypercalcaemia. Br J Radiol 1983;56:345–349.|
|53.||Moss DW, Henderson AR. Clinical enzymology. In: Burtis CA, Ashwood ER, editors. Tietz textbook of clinical chemistry. Philadelphia: W.B. Saunders; 1999. p. 617–721.|
|54.||Kim SW, Charter RA, Chai CJ, Kim SK, Kim ES. Serum alkaline phosphatase and inorganic phosphorus values in spinal cord injury patients with heterotopic ossification. Paraplegia 1990;28:441–447.|
|55.||Edelson JD, Shannon JM, Mason RJ. Alkaline phosphatase: a marker of alveolar type II cell differentiation. Am Rev Respir Dis 1988; 138:1268–1275.|
|56.||Gomori G. Calcification and phosphatase. Am J Pathol 1943;19:197–209.|
|57.||Abraham EP. Necrosis, calcification and autolysis. In: Florey L, editor. General pathology. London: Lloyd-Luke Medical Books; 1970. p. 431–450.|
|58.||Cotran RS, Kumar V, Robbins SL. Cellular injury and cellular death: pathologic basis of disease. Philadelphia: W.B. Saunders; 1994. p. 1–34.|
|59.||Akagawa KS, Takasuka N, Nozaki Y, Komuro I, Azuma M, Ueda M, Naito M, Takahashi K. Generation of CD1+RelB+ dendritic cells and tartrate-resistant acid phosphatase-positive osteoclast-like multi-nucleated giant cells from human monocytes. Blood 1996;88:4029–4039.|
|60.||Morii H, Ohnishi Y, Oko-moto T, Nishizawa Y, Miki T, Iba K, Wada M, Inoue T, Matsushita Y, Kikunami K. A case of B cell lymphoma complicated by hypercalcemia and acute respiratory insufficiency. Osaka City Med J 1983;29:75–85.|
|61.||Poe RH, Kamath C, Bauer MA, Qazi R, Kallay MC, Woll JE. Acute respiratory distress syndrome with pulmonary calcification in two patients with B cell malignancies. Respiration 1989;56:127–133.|
|62.||Yeh LC, Lee JC. Osteogenic protein-1 increases gene expression of vascular endothelial growth factor in primary cultures of fetal rat calvaria cells. Mol Cell Endocrinol 1999;153:113–124.|
|63.||Schurch B, Capaul M, Vallotton MB, Rossier AB. Prostaglandin E2 measurements: their value in the early diagnosis of heterotopic ossification in spinal cord injury patients. Arch Phys Med Rehabil 1997; 78:687–691.|
|64.||Wang DS, Yamazaki K, Nohtomi K, Shizume K, Ohsumi K, Shibuya M, Demura H, Sato K. Increase of vascular endothelial growth factor mRNA expression by 1,25-dihydroxyvitamin D3 in human osteoblast-like cells. J Bone Miner Res 1996;11:472–479.|
|65.||Harada S, Nagy JA, Sullivan KA, Thomas KA, Endo N, Rodan GA, Rodan SB. Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J Clin Invest 1994;93: 2490–2496.|
|66.||Alini M, Marriott A, Chen T, Abe S, Poole AR. A novel angiogenic molecule produced at the time of chondrocyte hypertrophy during endochondral bone formation. Dev Biol 1996;176:124–132.|
|67.||Brown RA, McFarland CD. Regulation of growth plate cartilage degradation in vitro: effects of calcification and a low molecular weight angiogenic factor (ESAF). Bone Miner 1992;17:49–57.|
|68.||McFarland CD, Brown RA, McLaughlin B, Ali SY, Weiss JB. Production of endothelial cell stimulating angiogenesis factor (ESAF) by chondrocyte during in vitro cartilage calcification. Bone Miner 1990; 11:319–333.|
|69.||Firooznia H, Pudlowski R, Golimbu C, Rafie M, McCauley D. Diffuse interstitial calcification of the lungs in chronic renal failure mimicking pulmonary edema. AJR Am J Roentgenol 1977;129:1103–1105.|
|70.||Mootz JR, Sagel SS, Roberts TH. Roentgenographic manifestations of pulmonary calcifications: a rare cause of respiratory failure in chronic renal disease. Radiology 1973;107:55–60.|
|71.||Smith JC, Stanton LW, Kramer NC, Parrish AE. Nodular pulmonary calcification in renal failure. Am Rev Respir Dis 1969;100:723–728.|
|72.||Hartman TE, Muller NL, Primack SL, Johkoh T, Takeuchi N, Ikezoe J, Swensen SJ. Metastatic pulmonary calcification in patients with hypercalcemia: Findings on chest radiographs and CT scans. AJR Am J Roentgenol 1994;162:799–802.|
|73.||Johkoh T, Ikezoe J, Nagareda T, Kohno N, Takeuchi N, Kozuka T. Metastatic pulmonary calcification: early detection by high-resolution CT. J Comput Assist Tomogr 1993;17:471–473.|
|74.||Gevenois PA, Abehsera M, Knoop C, Jacobovitz D, Estenne M. Disseminated pulmonary ossification in end-stage pulmonary fibrosis: CT demonstration. AJR Am J Roentgenol 1994;162:1303–1304.|
|75.||Taguchi Y, Fuyuno G, Shioya S, Yanagimachi N, Katoh H, Matsuyama S, Ohta Y. MR appearance of pulmonary metastatic calcification. J Comput Assist Tomogr 1996;20:38–41.|
|76.||Devacaanthan K, Yap AU, Chayes Z, Stein RM. Pulmonary calcification in chronic renal failure: use of diphosphonate scintiscan as a diagnostic tool. Clin Nephrol 1976;6:488–491.|
|77.||Grames GM, Sauser DD, Jansen C, Soderblom RE, Hodgkin JE, Stilson MS. Radionuclide detection of diffuse interstitial pulmonary calcification. JAMA 1974;230:992–995.|
|78.||Rosenthal DI, Chandler HL, Azizi F, Schneider PB. Uptake of bone imaging agents by diffuse pulmonary metastatic calcification. AJR Am J Roentgenol 1977;129:871–874.|
|79.||Bayat-Mokhtari F, Palmieri GMA, Moinuddin M, Pourmand R. Parathyroid storm. Arch Intern Med 1980;140:1092–1095.|
|80.||Hirano T, Otake H, Ichikawa K, Ohmori Y, Kunitomo K. Metastatic calcification: difference of uptake between Tc-99m HMDP and Ga-67 citrate. Clin Nucl Med 1995;20:849–850.|
|81.||Sullivan WT, Orzel JA, Reed KD, Bower JH. Abnormal lung and liver uptake of gallium-67 and technetium-99m MDP in hypercalcemia of lymphoma with metastatic pulmonary calcification. Clin Nucl Med 1986;11:545–548.|
|82.||Lecklitner ML, Foster RW. Absence of gallium-67 avidity in diffuse pulmonary calcification. Clin Nucl Med 1985;10:632–634.|
|83.||Coolens J-L, Devos P, De Roo M. Diffuse pulmonary uptake of 99mTc bone-imaging agents: case report and survey. Eur J Nucl Med 1985; 11:36–42.|
|84.||Conger JD, Alfrey AC. Scanning for pulmonary calcification [letter]. Ann Intern Med 1976;84:224–225.|
|85.||Faubert PF, Shapiro WB, Porush JG, Chou S-Y, Gross JM, Bondi E, Gomez-Leon G. Pulmonary calcification in hemodialyzed patients detected by technetium-99m diphosphonate scanning. Kidney Int 1980;18:95–102.|
|86.||Kaltreider HB, Baum GL, Bogaty A, McCoy MD, Tucker M. Calcification of the lung. Am J Med 1969;46:188–196.|
|87.||Holmes RA. Diffuse interstitial pulmonary calcification. JAMA 1974; 230:1018–1019.|
|88.||Kuhlman JE, Ren H, Hutchins GM, Fishman EK. Fulminant pulmonary calcification complicating renal transplantation: CT demonstration. Radiology 1989;173:459–460.|
|89.||Wang N-S, Steele AA. Pulmonary calcification: scanning electron microscopic and X-ray energy-dispersive analysis. Arch Pathol Lab Med 1979;103:252–253.|
|90.||Contiguglia SR, Alfrey AC, Miller NL. Nature of soft tissue calcification in uremia. Kidney Int 1973;4:229–235.|
|91.||Fulladosa X, Gonzales MT, Cruzado JM, Andres E, Castelao AM, Grino JM, Alsina J. Metastatic calcifications in severe secondary hyperparathyroidism: evolution after renal transplantation. Transplant Proc 1995;27:2272–2276.|
|92.||Ullmer E, Borer H, DSandoz P, Mayr M, Dalquen P, Soler M. Diffuse pulmonary nodular infiltrates in a renal transplant recipient. Chest 2001;120:1394–1398.|
|93.||Zouboulis CC, Blume-Peytavi U, Lennert T, Stavropoulos PG, Schwarz A, Runkel N, Trautmann C, Orfanos CE. Fulminant metastatic calcinosis with cutaneous necrosis in a child with end-stage renal disease and tertiary hyperparathyroidism. Br J Dermatol 1996;135:617–622.|
|94.||Uchida M, Sakemi T, Ikeda Y, Maeda T. Acute progressive and extensive metastatic calcifications in a nephrotic patient following chronic hemodialysis. Am J Nephrol 1995;15:427–430.|
|95.||Giachelli CM, Jono S, Shioi A, Nishizawa Y, Mori K, Morii H. Vascular calcification and inorganic phosphate. Am J Kidney Dis 2001;38:S34–S37.|
|96.||Breitz HB, Sirotta PS, Nelp WB, Ott S, Figley MM. Progressive pulmonary calcification complicating successful renal transplantation. Am Rev Respir Dis 1987;136:1480–1482.|
|97.||Murris-Espin M, Lacassagne L, Didier A, Voigt JJ, Cisterne JM, Giron J, Durand D, Leophonte P. Metastatic pulmonary calcification after renal transplantation. Eur Respir J 1997;10:1925–1927.|
|98.||Mine Y, Ito N, Tagawa M, Imamura K, Mori I, Kitamura T, Nakano M, Shigematsu K. Metastatic calcification associated with malignancy. Jpn J Cancer Clin 1988;34:2044–2051.|
|99.||Davidson RC, Pendros JP. Calcium related cardio-respiratory death in chronic hemodialysis. Trans Am Soc Artif Intern Organs 1967;13:36–40.|
|100.||Northcutt AD, Tio FO, Chamblin SA, Britton HA. Massive metastatic pulmonary calcification in an infant with aleukemic monocytic leukemia. Pediatr Pathol 1985;4:219–229.|
|101.||Ghadially FN. As you like it. III. A critique and historical review of calcification as seen with the electron microscope. Ultrastruct Pathol 2001;25:243–267.|
|102.||Milliner DS, Lieberman E, Landing BH. Pulmonary calcinosis after renal transplantation in pediatric patients. Am J Kidney Dis 1986;7: 495–501.|
|103.||Gurney JW, Conces DJ. Pulmonary histoplasmosis: state of the art. Radiology 1996;199:297–306.|
|104.||Palayew MJ, Frank H. Benign progressive multinodular pulmonary histoplasmosis: a radiological and clinical entity. Radiology 1974;111: 311–314.|
|105.||Rubin SA, Winer-Muram HT. Thoracic histoplasmosis. J Thorac Imaging 1992;7:39–50.|
|106.||Abbasi AA, Chemplavi JK, Farah S, Muller BF, Arnstein AR. Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med 1979;90: 324–328.|
|107.||Murray JJ, Heim CR. Hypercalcemia in disseminated histoplasmosis: aggravation by vitamin D. Am J Med 1985;78:881–884.|
|108.||Stern PH, DeOlazzabal J, Bell NH. Evidence for abnormal regulation of circulating 1α,25-dihydroxyvitamin D in patients with sarcoidosis and normal calcium metabolism. J Clin Invest 1980;66:852–855.|
|109.||Batra P. Pulmonary coccidioidomycosis. J Thorac Imaging 1992;7:29–38.|
|110.||Roussos A, Lagogianni I, Gonis A, Ilias I, Kazi D, Patsopoulos D, Philippou N. Hypercalcaemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment. Respir Med 2001;95: 187–190.|
|111.||Weinstein DS. Pulmonary sarcoidosis: calcified micronodular pattern simulating pulmonary alveolar microlithiasis. J Thorac Imaging 1999; 14:218–220.|
|112.||Jones EL, Cameron AH. Pulmonary calcification in viral pneumonia. J Clin Pathol 1969;22:361–366.|
|113.||Knyvett AF. The pulmonary lesions of chickenpox. Q J Med 1966;35: 313–323.|
|114.||Foster DR. Case report: pulmonary calcification in smallpox handler's lung. Br J Radiol 1994;67:599–600.|
|115.||Mannhardt W, Schumacher R. Progressive calcifications of lung and liver in neonatal herpes simplex infection. Pediatr Radiol 1991;21:236–237.|
|116.||Blumenfeld W, Basgoz N, Owen WF, Schmidt DM. Granulomatous pulmonary lesions in patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii infection. Ann Intern Med 1988;109:505–507.|
|117.||LeGolvan DP, Heidelberger KP. Disseminated granulomatous Pneumocystis carinii pneumonia. Arch Pathol 1973;95:344–348.|
|118.||Niedt GW, Schinella RA. Acquired immunodeficiency syndrome: clinicopathologic study of 56 autopsies. Arch Pathol 1985;109:727–734.|
|119.||Travis WD, Pittaluga S, Lipschik GY, Ognibene FP, Suffredini AF, Masur H, Feuerstein IM, Kovacs J, Pass HI, Condron KS, et al. Atypical pathologic manifestations of Pneumocystis carinii pneumonia in the acquired immune deficiency syndrome: review of 123 lung biopsies from 76 patients with emphasis on cysts, vascular invasion, vasculitis and granulomas. Am J Surg Pathol 1990;14:615–625.|
|120.||Feuerstein IM, Francis P, Raffeld M, Pluda J. Widespread visceral calcifications in disseminated Pneumocystis carinii infection: CT characteristics. J Comput Assist Tomogr 1990;14:149–151.|
|121.||Groskin SA, Massi AF, Randall PA. Calcified hilar and mediastinal lymph nodes in an AIDS patient with Pneumocystis carinii infection. Radiology 1990;175:345–346.|
|122.||Srivatsa SS, Burger CD, Douglas WW. Upper lobe pulmonary parenchymal calcification in a patient with AIDS and Pneumocystis carinii pneumonia receiving aerosolized pentamidine. Chest 1992;101:266–267.|
|123.||Levine E. Abdominal visceral calcification in secondary amyloidosis: CT findings. Abdom Imaging 1994;19:554–555.|
|124.||Kim HY, Im JG, Song KS, Lee KS, Kim SJ, Kim JS, Lee JS, Lim TH. Localized amyloidosis of the respiratory system: CT features. J Comput Assist Tomogr 1999;23:627–631.|
|125.||Laden SA, Cohen ML, Harley RA. Nodular pulmonary amyloid with extrapulmonary involvement. Human Pathol 1984;15:594–597.|
|126.||Webb WR, Muller NL, Naidich DP. Diseases characterized primarily by nodular or reticulonodular opacities: high-resolution CT of the lung, 2nd ed. Philadelphia: Lippincott-Raven; 1996. p. 149–191.|
|127.||Heath D, Wood EH, DuShane JW, Edwards JE. The relation of age and blood pressure to atheroma in the pulmonary arteries and thoracic aorta in congenital heart disease. Lab Invest 1960;9:259–272.|
|128.||Anderson TJ, Larsen ET, Wyse G, Lester WM. Primary pulmonary hypertension for 30 years. Am J Cardiol 1991;68:284–285.|
|129.||Botney MD, Kaiser LR, Cooper JD, Meacham RP, Parghi D, Roby J, Parks WC. Extracellular matrix protein gene expression in atherosclerotic hypertensive pulmonary arteries. Am J Pathol 1992;140:357–364.|
|130.||Wagenvoort CA, Heath D, Edwards JE. The pathology of the human vasculature. Springfield, IL; Charles C. Thomas; 1964.|
|131.||Bostrom K, Watson KE, Stanford WP, Demer LL. Atherosclerotic calcification relation to developmental osteogenesis. Am J Cardiol 1995; 75:88B–91B.|
|132.||Doherty MJ, Canfield AE. Gene expression during vascular pericyte differentiation. Crit Rev Eukaryot Gene Expr 1999;9:1–17.|
|133.||Christou H, Yoshica A, Arthur V, Morita T, Kourembanas S. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 1998;18:768–776.|
|134.||Tomizawa Y, Takanashi Y, Noishiki Y, Nishida H, Emdo M, Koyanagi H. Evaluation of small caliber vascular prostheses implanted in small children: activated angiogenesis and accelerated calcification. ASAIO J 1998;44:496–500.|
|135.||Popek EJ, Strain JD, Neumann A, Wilson H. In utero development of pulmonary artery calcification in monochorionic twins: a report of three cases and discussion of the possible etiology. Pediatr Pathol 1993;13:597–611.|
|136.||Tamiya E, Asakawa M, Ando H, Ito N, Ikenouchi H, Hada Y, Tanaka K, Murota Y, Ando T, Furuse A. Pulmonary artery calcification in contact with a left coronary artery bypass graft: an X-ray computed tomographic study. Int J Angiol 2001;10:53–57.|
|137.||Chanda J, Kuribayashi R, Abe T. Heparin coupling in inhibition of calcification of vascular prostheses. Biomaterials 1999;20:1753–1757.|
|138.||Steinberg I. Calcification of pulmonary artery and enlargement of right ventricle: a sign of congenital heart disease, Eisenmenger syndrome, pulmonary hypertension, increased pulmonary artery resistance and reversal of blood flow. AJR Am J Roentgenol 1966;98:369–377.|
|139.||Cohen BA, Gale JT, Mendelson DS, Mitty HA. Computer tomography demonstration of pulmonary artery calcification in Eisenmenger's syndrome. J Comput Tomogr 1985;99:153–156.|
|140.||Philip T. Pulmonary artery calcification. Scott Med J 1972;17:104–107.|
|141.||Pochaczevsky R, Dunst ME. Coexistent pulmonary artery and aortic arch calcification: its significance and association with patent ductus arteriosus. Am J Roentgenol Radium Ther Nucl Med 1972;116:141–145.|
|142.||Bird T. Idiopathic arterial calcification in infancy. Arch Dis Child 1974;49:82–89.|
|143.||Moe SM, O'Neill KD, Duan D, Ahmed S, Chen NX, Leapman SB, Fineberg N, Kopecky K. Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int 2002;61:638–647.|
|144.||Barnard NJ, Crocker PR, Blainey AD, Davies RJ, Ell SR, Levison DA. Pulmonary alveolar microlithiasis: a new analytical approach. Histopathology 1987;11:639–645.|
|145.||Coetzee T. Pulmonary alveolar microlithiasis with involvement of the sympathetic nervous system and gonads. Thorax 1970;25:637–642.|
|146.||Sosman MC, Dodd GD, Jones WD, Pillmore GU. The familial occurrence of pulmonary alveolar microlithiasis. AJR Am J Roentgenol 1957;77:947–1012.|
|147.||Ucan ES, Keyf AI, Aydilek R, Yalcin Z, Sebit S, Kudu M, Ok U. Pulmonary alveolar microlithiasis: review of Turkish reports. Thorax 1993;48:171–173.|
|148.||Bogart SD. Disseminated pulmonary calcinosis with pulmonary alveolar microlithiasis. NY State J Med 1980;80:1283–1284.|
|149.||Cluzel P, Grenier P, Bernadac P, Laurent F, Picard JD. Pulmonary alveolar microlithiasis: CT findings. J Comput Assist Tomogr 1991;15: 938–942.|
|150.||Chai JL, Patz EF. CT of the lung: patterns of calcification and other high-attenuation abnormalities. AJR Am J Roentgenol 1994;162:1063–1066.|
|151.||Gocmen A, Toppare MF, Kiper N, Buyukpamukcu N. Treatment of pulmonary alveolar microlithiasis with a diphosphonate: preliminary results of a case. Respiration 1992;59:250–252.|
|152.||Richardson J, Slovis B, Miller G, Dummer S. Development of pulmonary alveolar microlithiasis in a renal transplant recipient. Transplantation 1995;59:1056–1057.|
|153.||Freiberg DB, Young IH, Laks L, Regnis JA, Lehrhaft B, Sullivan CE. Improvement in gas exchange with nasal continuous positive airway pressure in pulmonary alveolar microlithiasis. Am Rev Respir Dis 1992;145:1215–1216.|
|154.||Epstein EJ, Chapman R, Coudshed N, Galloway RW. Pulmonary ossific nodule formation in the absence of mitral valve disease. Am Heart J 1963;65:816–825.|
|155.||Felson B, Schwarz J, Lukin RR, Hawkins HH. Idiopathic pulmonary ossification. Radiology 1984;153:303–310.|
|156.||Joines RW, Roggli VL. Dendriform pulmonary ossification: report of two cases with unique findings. Am J Clin Pathol 1989;91:398–402.|
|157.||Kuplic JB, Higley CS, Niewoehner DE. Pulmonary ossification associated with long-term busulfan therapy in chronic myeloid leukemia: case report. Am Rev Respir Dis 1972;106:759–762.|
|158.||Mendeloff J. Disseminated nodular pulmonary ossification in the Hamman-Rich lung. Am Rev Respir Dis 1971;103:269–277.|
|159.||Ndimbie OK, Williams CR, Lee MW. Dendriform pulmonary ossification. Arch Pathol Lab Med 1987;111:1062–1064.|
|160.||Pear BL. Idiopathic disseminated pulmonary ossification. Radiology 1968; 91:746–748.|
|161.||Chow IT, Shum BSF, Chow WH, Tso CB. Diffuse pulmonary ossification: rare complications of tuberculosis. Histopathology 1992;20:435–437.|
|162.||Kayser K, Stute H, Tuengerthal S. Diffuse pulmonary ossification associated with metastatic melanoma of the lung. Respiration 1987;52: 221–227.|
|163.||Green JD, Harle TS, Greenberg SD, Weg JG, Nevin H, Jenkins DE. Disseminated pulmonary ossification. Am Rev Respir Dis 1970;101: 293–298.|
|164.||Schwarz MI, King TE, editors. Interstitial lung disease, 3rd ed. Hamilton, Ontario: B.C. Decker; 1998.|
|165.||Maiti SK, Singh GR. Bone morphogenic proteins: novel regulators of bone formation. Indian J Exp Biol 1998;36:237–244.|
|166.||Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 2000;26:81–84.|
|167.||Muramatsu T, Hamano H, Fukumashi K, Shiigai T, Fujiseki M, Katayanagi T, Osada K, Inoue T, Shimono M. An experimental study of chondrogenesis and osteogenesis in rat submandibular gland induced by implantation of demineralized dentin. Bull Tokyo Dent Coll 1993;34:15–22.|
|168.||Mahy PR, Urist MR. Experimental heterotopic bone formation induced by bone morphogenetic protein and recombinant human interleukin-β. Clin Orthop 1988;237:236–244.|
|169.||Fried ED, Godwin TA. Extensive diffuse pulmonary ossification. Chest 1992;102:1614–1615.|
|170.||Popelka CG, Kleinerman J. Diffuse pulmonary ossification. Arch Intern Med 1977;137:523–525.|
|171.||Reddi AH, Huggins CB. Cyclic electrochemical inactivation and restoration of competence of bone matrix to transform fibroblasts. Proc Natl Acad Sci USA 1974;71:1648–1652.|
|172.||Buja LM, Roberts WC. Pulmonary parenchymal ossific nodules in idiopathic hypertrophic subaortic stenosis. Am J Cardiol 1970;25:710–715.|
|173.||Galloway R, Epstein EJ, Coulshed N. Pulmonary ossific nodules in mitral valve disease. Br Heart J 1961;23:297–307.|
|174.||Whitaker W, Black A, Warrack AJN. Pulmonary ossification in patients with mitral stenosis. J Fac Radiologists 1955;7:29–34.|
|175.||Rajjoub S, Altmeyer RB. A case report of idiopathic pulmonary ossification. W V Med J 1998;94:143–145.|
|176.||Saks DA, McClees EC, Fajman WA, Hollinger WM, Gilman MJ. Diffuse pulmonary ossification detected by bone scanning with Tc-99m hydroxymethylene diphosphate. Clin Nucl Med 1984;9:594–595.|
|177.||Silberstein EB, Vasavada PJ, Hawkins H. Idiopathic pulmonary ossification with focal pulmonary uptake of technetium-99m HMDP bone scanning agent. Clin Nucl Med 1985;10:436.|